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Introduction: A recent study on patients with acute lower limb ischemia showed that the proportion of inadequate examination of lower extremity circulation was associated with higher rate of amputation and death. The aim of this systematic review was to explore evidence for how practical competence in performing a peripheral vascular status of the lower limb among medical students and junior doctors should be taught and examined., Methods: The systematic review followed PRISMA guidelines and was published in PROSPERO. Articles were searched for in PubMed, Cochrane Library and Embase. The result was processed by two researchers. After title- and abstract screenings, articles were scrutinized in full text for inclusion, result extraction, risk of bias assessment through Medical Education Research Study Quality Instrument (MERSQI), and evidence grading with the GRADE approach., Results: Thirteen studies were included. Two studies were randomized controlled trials (RCTs). Study samples varied between medical students (n = 9), junior doctors (n = 3) and residents (n = 3). Interventions varied between theoretical, practical, repetitive training, feedback-based learning, and clinical experience. Assessed measurements (outcomes) were ankle-brachial index (ABI) (n = 9), theoretical knowledge (n = 4), pulse palpation (n = 1) and complete vascular status (n = 1). Experienced residents had better theoretical knowledge than inexperienced residents, but performance of the entire ABI procedure without any mistake according to guidelines was inadequate in both groups. One RCT showed that experimental training significantly increased ability to perform ABI measurements, but this ability decreased after six months without repetition., Conclusion: Theoretical training alone is not sufficient in ensuring proficiency in vascular examination of the lower limbs. Continuous practice and clinical exposure are crucial to maintain proficiency in performing vascular examination of the lower limbs. Data is limited and heterogenous. The level of certainty for the evidence was judged to be very low., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Objectives: This study evaluated the psychometric properties of the ceroid lipofuscinosis type 2 Quality of Life (CLN2 QoL) questionnaire., Methods: Data from children with CLN2 disease aged 3-16 years receiving cerliponase alfa in the BMN 190-201 and BMN 190-202 clinical studies, collected via purposive sampling, were used to assess convergent and divergent validity, internal consistency and reliability. The clinically important difference (CID) was estimated with distribution- and anchor-based methods. Descriptive and inferential statistical analyses were conducted using IBM SPSS., Results: CLN2 QoL data of 22 participants were analysed. Ceiling effects were observed in 22 items (35% threshold); no floor effects were observed. Internal consistency analysis showed good reliability (Cronbach's alpha and Omega reliability >0.7) for four domains at study completion; only one domain had good reliability at baseline. All domains had good test-retest reliability (correlation >0.5) except Feeding With G-Tube and Seizures. Convergent and divergent correlation analysis showed moderate-strong correlations (>0.4) between PedsQL and CLN2 QoL total scores, between the Pediatric Quality of Life Inventory (PedsQL) total score and most CLN2 QoL domains at baseline, and between CLN2 QoL total score and most PedsQL domains at week 97. Known groups validity showed a significant difference in means for the Behaviour domain ( p = 0.05) for reasons that could not be clarified. CID was 6.79-12.94 for domains; total score CID was 6.91 using distribution-based and 6.13-13.05 using anchor-based methods., Conclusions: This study is the first to validate the CLN2 QoL and to estimate the CID of this instrument in CLN2 patients. Our results show good validity and reliability of this tool.

Global warming has become a much more realised issue and an immediate threat, accelerating due to the anthropogenic carbon release associated with escalating energy demand. Consequently, pressures are building up to reduce anthropogenic carbon footprint by employing renewable energy resources, among which solar energy is the main. Solar roads are a new and innovative concept as they do not require land to be specifically allocated. This is because the road infrastructure already exists. Therefore, this emerging technique of embedding solar panels into pavements and roadways is becoming a more attractive proposition. However, a hurdle to its successful application is the lack of knowledge regarding its feasibility and viability. This study aims to evaluate the potential of solar roads to inform future feasibility and viability studies in varying contexts and implications. Within the scope of this study, the case of Great Britain is considered to evaluate the potential of how much energy can be generated via the solar roads technology that can be embedded in the country's road infrastructure. A mathematical exercise is performed in which calculations are executed to develop a basic numerical model of the potential. Therefore, the study is quantitative, and the factors considered include seasonal changes, average daily traffic covering roads, tree and building shades, road types and sizes, solar irradiance, solar panel types, and alike. It is estimated that solar roads may supply up to 96.42% of the UK's total electricity, which is a substantially promising potential.

Entomopathogenic fungi belonging to the Order Hypocreales are renowned for their ability to infect and kill insect hosts, while their endophytic mode of life and the beneficial rhizosphere effects on plant hosts have only been recently recognized. Understanding the molecular mechanisms underlying their different lifestyles could optimize their potential as both biocontrol and biofertilizer agents, as well as the wider appreciation of niche plasticity in fungal ecology. This study describes the comprehensive whole genome sequencing and analysis of one of the most effective entomopathogenic and endophytic EPF strains, Metarhizium brunneum V275 (commercially known as Lalguard Met52), achieved through Nanopore and Illumina reads. Comparative genomics for exploring intraspecies variability and analyses of key gene sets were conducted with a second effective EPF strain, M. brunneum ARSEF 4556. The search for strain- or species-specific genes was extended to M. brunneum strain ARSEF 3297 and other species of genus Metarhizium, to identify molecular mechanisms and putative key genome adaptations associated with mode of life differences. Genome size differed significantly, with M. brunneum V275 having the largest genome amongst M. brunneum strains sequenced to date. Genome analyses revealed an abundance of plant-degrading enzymes, plant colonization-associated genes, and intriguing intraspecies variations regarding their predicted secondary metabolic compounds and the number and localization of Transposable Elements. The potential significance of the differences found between closely related endophytic and entomopathogenic fungi, regarding plant growth-promoting and entomopathogenic abilities, are discussed, enhancing our understanding of their diverse functionalities and putative applications in agriculture and ecology., Competing Interests: Conflicts of interest The author(s) declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

Neural tube closure in vertebrates is achieved through a highly dynamic and coordinated series of morphogenic events involving neuroepithelium, surface ectoderm, and neural plate border. Failure of this process in the caudal region causes spina bifida. Grainyhead-like 3 (GRHL3) is an indispensable transcription factor for neural tube closure as constitutive inactivation of the Grhl3 gene in mice leads to fully penetrant spina bifida. Here, through single-cell transcriptomics we show that at E8.5, the time-point preceding mouse neural tube closure, co-expression of Grhl3 , Tfap2a , and Tfap2c defines a previously unrecognised progenitor population of surface ectoderm integral for neural tube closure. Deletion of Grhl3 expression in this cell population using a Tfap2a-Cre transgene recapitulates the spina bifida observed in Grhl3 -null animals. Moreover, conditional inactivation of Tfap2c expression in Grhl3 -expressing neural plate border cells also induces spina bifida. These findings indicate that a specific neural plate border cellular cohort is required for the early-stage neurulation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: The CLN2 Clinical Rating Scale evaluates disease progression in CLN2 disease, an ultra-rare, neurodegenerative disorder with late infantile onset. To validate the Clinical Rating Scale, a comparison with the Pediatric Quality of Life Inventory (PedsQL) was conducted utilising clinical trial data investigating cerliponase alfa use in CLN2 disease., Methods: Linear regression and mixed effects models were used to investigate the relationship between the Clinical Rating Scale and PedsQL using open-label, single-arm, phase 1/2 (NCT01907087) and ongoing extension study (NCT02485899) data of 23 children with CLN2 disease treated with cerliponase alfa for ≥96 weeks., Results: Correlations between the four Clinical Rating Scale domains were low. Linear mixed effects analyses showed significant correlation between PedsQL and Clinical Rating Scale (Total score or motor-language [ML] score adjusted p-values <0.05), driven by the relationship with the PedsQL Physical domain. A statistically significant relationship was identified between the Clinical Rating Scale motor domain and PedsQL (Total score: adjusted p-value = 0.048, parameter estimate [PE] = 8.10; Physical domain score: adjusted p-value = 0.012; PE = 13.79)., Conclusions: Each domain of the Clinical Rating Scale provides unique information on disease state. Validity of the scale is supported by its relationship with the PedsQL. Among the four domains of the Clinical Rating Scale, motor has the highest correlation to PedsQL, suggesting motor function as a driver of patients' quality of life. The lack of association between the remaining domains of the Clinical Rating Scale and PedsQL suggests that additional disease-specific measures may be needed to fully capture the quality of life impact of CLN2 disease., Trial Registration: NCT01907087, NCT02485899., Competing Interests: PG, NS: No competing interests to declare; AS: Received compensation from BioMarin Europe as per clinical trial agreement; EdlR: Research grants from Amicus Therapeutics, BioMarin Pharmaceutical Inc., Giving Back Fund; Consultancy: BioMarin Pharmaceuticals Inc.; AO, CC, TB, and MJ: Employees and shareholders of BioMarin Europe; ZS: Employee of BioMarin Europe; TC and AG: Employees of Costello Medical; JCP and PS: Employees and shareholders of BioMarin Pharmaceutical Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Specchio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Incisional negative pressure wound therapy (iNPWT) applied over all incisions after lower extremity bypass in the prevention of surgical site infections (SSIs) is unclear. The primary and secondary aims of this study were to investigate if prophylactic iNPWT after the elective lower extremity bypass prevents SSI and other surgical wound complications., Methods: This was a multicenter, parallel, randomized controlled trial. Patients undergoing elective lower extremity bypass in 3 hospitals were randomized to either iNPWT or standard dressings. SSIs or other wound complications were assessed within the first 90 days by wound care professionals blinded to the randomized result. The validated Additional treatment, Serous discharge, Erythema, Purulent exudate, Separation of deep tissues, Isolation of bacteria, and Stay (ASEPSIS) score was used to objectively assess the wounds. ASEPSIS score ≥21 is defined as an SSI. Unilateral and bilateral groups were analyzed with the Fisher exact test and the McNemar test, respectively., Results: In the unilateral group (n = 100), the incidence of SSI in the iNPWT group was 34.9% (15/43), compared with 40.3% (23/57) in the control group, according to the ASEPSIS score (P = .678). In the bilateral group (n = 7), the SSI rate was 14.3% (1/7) in the iNPWT group compared with 14.3% (1/7) in the control group (P = 1.00). In the unilateral group, there was a higher wound dehiscence rate in the control group (43.9%) compared with the iNPWT group (23.3%) (P = .0366). No serious iNPWT-related adverse events were recorded., Conclusions: There was no reduction of SSI rates in leg incisions with iNPWT compared with standard dressings in patients undergoing elective lower extremity bypass, whereas iNPWT reduced the incidence of wound dehiscence., Competing Interests: Disclosures None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Previous reports have suggested higher rates of mortality and amputation for female patients in acute lower limb ischemia (ALI). The aims of the present study were to investigate if there is a difference in mortality, amputation, and fasciotomy between the sexes., Methods: A retrospective cohort study of consecutive patients undergoing index revascularization for ALI between 2001 and 2018 was conducted. A propensity score was created through a logistic regression with female/male sex as an outcome. Cox regression analyses for 90-day and 1-year mortality, combining major amputation/mortality, and logistic regression for major bleeding and fasciotomy, were performed. All analyses were performed with and without adjusting for propensity score., Results: A total of 709 patients were included in the study of which 45.9% were women. Mean age was 72.1 years. Females were older and had higher rates of atrial fibrillation, embolic disease, and lower estimated glomerular filtration rate, while men more often had anemia and chronic peripheral arterial disease. Mortality at 1 year was 21.2% for women and 14.7% for men. The adjusted hazard ratio for 1-year mortality was 0.99 (95% CI 0.67-1.46). Fasciotomy was performed in 7.1% of female and 12.8% of male patients; the adjusted odds ratio was 0.52 (95% CI 0.29-0.91)., Conclusion: Sex was not found to be an independent risk factor for mortality or combined major amputation/mortality after revascularization for acute lower limb ischemia, whereas women had lower odds of undergoing fasciotomy. Whether women are underdiagnosed or do not develop acute compartment syndrome in the lower leg as often as men should be evaluated prospectively., (© 2024 International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Intersectoral processes that bring together public institutions, civil society organizations and affected community members are essential to tackling complex health equity challenges. While conventional wisdom points to the importance of human relationships in fostering collaboration, there is a lack of practical guidance on how to do intersectoral work in ways that support authentic relationship-building and mitigate power differentials among people with diverse experiences and roles. This article presents the results of RentSafe EquIP, a community-based participatory research initiative conducted in Owen Sound, Canada, in the midst of a housing crisis. The research explored the potential utility of equity-focused intersectoral practice (EquIP), a novel approach that invests in human relationships and knowledge co-creation among professionals and affected members of the community. The three-phase EquIP methodology centred the grounded expertise of community members with lived/living experience of housing inadequacy to catalyze reflexive thinking by people in professional roles about the institutional gaps and barriers that prevent effective intersectoral response to housing-related inequities. The research demonstrated that EquIP can support agency professionals and community members to (i) engage in (re)problematization to redefine the problem statement to better include upstream drivers of inequity, (ii) support reflexivity among those in professional roles to identify institutional practices, policies and norms that perpetuate stigma and impede effective intersectoral response and (iii) spark individual and collective agency and commitment towards a more equity-focused intersectoral system. We conclude that the EquIP methodology is a promising approach for communities seeking to address persistent health equity and social justice challenges., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: This multicenter international study aimed to describe outcomes of fenestrated-branched endovascular aortic repairs (FB-EVAR) in a cohort of patients treated for chronic post-dissection thoracoabdominal aortic aneurysms (PD-TAAAs)., Methods: We reviewed the clinical data of all consecutive patients treated by FB-EVAR for repair of extent I to III PD-TAAAs in 16 centers from the United States and Europe (2008-2021). Data were extracted from institutional prospectively maintained databases and electronic patient records. All patients received off-the-shelf or patient-specific manufactured fenestrated-branched stent grafts. Endpoints were any cause mortality and major adverse events at 30 days, technical success, target artery (TA) patency, freedom from TA instability, minor (endovascular with <12 Fr sheath) and major (open or ≥12 Fr sheath) secondary interventions, patient survival, and freedom from aortic-related mortality (ARM)., Results: A total of 246 patients (76% male; median age, 67 years [interquartile range, 61-73 years]) were treated for extent I (7%), extent II (55%), and extent III (35%) PD-TAAAs by FB-EVAR. The median aneurysm diameter was 65 mm (interquartile range, 59-73 mm). Eighteen patients (7%) were octogenarians, 212 (86%) were American Society of Anesthesiologists class ≥3, and 21 (9%) presented with contained ruptured or symptomatic aneurysms. There were 917 renal-mesenteric vessels targeted by 581 fenestrations (63%) and 336 directional branches (37%), with a mean of 3.7 vessels per patient. Technical success was 96%. Mortality and rate of major adverse events at 30 days was 3% and 28%, including disabling complications such as new onset dialysis in 1%, major stroke in 1%, and permanent paraplegia in 2%. Mean follow-up was 24 months. Kaplan-Meier (KM) estimated patient survival at 3 and 5 years was 79% ± 6% and 65% ± 10%. KM estimated freedom from ARM was 95% ± 3% and 93% ± 5% at the same intervals. Unplanned secondary interventions were needed in 94 patients (38%), including minor procedures in 64 (25%) and major procedures in 30 (12%). There was one conversion to open surgical repair (<1%). KM estimated freedom from any secondary intervention was 44% ± 9% at 5 years. KM estimated primary and secondary TA patency were 93% ± 2% and 96% ± 1% at 5 years, respectively., Conclusions: FB-EVAR for chronic PD-TAAAs was associated with high technical success and a low rate of mortality (3%) and disabling complications at 30 days. Although the procedure is effective in the prevention of ARM, patient survival was low at 5 years (65%), likely due to the significant comorbidities in this cohort of patients. Freedom from secondary interventions at 5 years was 44%, although most procedures were minor. The significant rate of reinterventions highlights the need for continued patient surveillance., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Pharmaco-mechanical thrombolysis (PMT) has emerged as a treatment option in patients with acute lower limb ischemia (ALI), especially Rutherford IIb (motor deficit) for rapid revascularization, but supportive data is scarce. The aim of the present study was to compare the effects of thrombolysis, complications, and outcomes of PMT first versus catheter-directed thrombolysis (CDT) first in a large cohort of patients with ALI., Methods: All endovascular thrombolytic/thrombectomy events in patients with ALI performed between January 1st, 2009, and December 31st, 2018 (n = 347) were included. Successful thrombolysis/thrombectomy was defined as complete or partial lysis. Reasons for using PMT were described. Complications such as major bleeding, distal embolization, and new onset of renal impairment, and major amputation and mortality at 30 days were compared between PMT (AngioJet) first and CDT first groups in a multivariable logistic regression model with adjustment for age, gender, atrial fibrillation, and Rutherford IIb., Results: The most common reason for initial use of PMT was the need for rapid revascularization, and the most common reason for use of PMT after CDT was the insufficient effect of CDT. Presentation of Rutherford IIb ALI was more common in the PMT first group (36.2% vs. 22.5%, respectively, P = 0.027). Among the 58 patients receiving PMT first, 36 (62.1%) were terminated within a single session of therapy without need of CDT. The median duration of thrombolysis was shorter (P < 0.001) for the PMT first group (n = 58) compared to the CDT first group (n = 289) (4.0 hr vs. 23.0 hr, respectively). There was no significant difference in amount of tissue plasminogen activator given, successful thrombolysis/thrombectomy (86.2% and 84.8%), major bleeding (15.5% and 18.7%), distal embolization (25.9% and 16.6%), major amputation or mortality at 30-days (13.8% and 7.7%) in the PMT first compared to the CDT first group, respectively. The proportion of new onset of renal impairment was higher in the PMT first compared to the CDT first group (10.3% vs. 3.8%, respectively), and the increased odds (odds ratio 3.57, 95% confidence interval 1.22-10.41) were maintained in the adjusted model. In Rutherford IIb ALI, no difference in rate of successful thrombolysis/thrombectomy (76.2% and 73.8%), complications or 30-day outcomes was found between PMT first (n = 21) and CDT (n = 65) first group., Conclusions: PMT first appears to be a good treatment alternative to CDT in patients with ALI, including Rutherford IIb. The found renal function deterioration in the PMT first group needs to be evaluated in a prospective, preferably randomized trial., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background/aims: To further validate the Vision Impairment in Low Luminance (VILL) questionnaire, which captures visual functioning and vision-related quality of life (VRQoL) under low luminance, low-contrast conditions relevant to age-related macular degeneration (AMD)., Methods: The VILL was translated from German into English (UK), Danish, Dutch, French, Italian and Portuguese. Rasch analysis was used to assess psychometric characteristics of 716 participants (65% female, mean age 72±7 years, 82% intermediate AMD) from the baseline visit of the MACUSTAR study. In a subset of participants (n=301), test-retest reliability (intraclass correlation coefficient (ICC) and coefficient of repeatability (CoR)) and construct validity were assessed., Results: Four items were removed from the VILL with 37 items due to misfit. The resulting Vision Impairment in Low Luminance with 33 items (VILL-33) has three subscales with no disordered thresholds and no misfitting items. No differential item functioning and no multidimensionality were observed. Person reliability and person separation index were 0.91 and 3.27 for the Vision Impairment in Low Luminance Reading Subscale (VILL-R), 0.87 and 2.58 for the Vision Impairment in Low Luminance Mobility Subscale (VILL-M), and 0.78 and 1.90 for the Vision Impairment in Low Luminance Emotional Subscale (VILL-E). ICC and CoR were 0.92 and 1.9 for VILL-R, 0.93 and 1.8 for VILL-M and 0.82 and 5.0 for VILL-E. Reported VRQoL decreased with advanced AMD stage (p<0.0001) and was lower in the intermediate AMD group than in the no AMD group (p≤0.0053)., Conclusion: The VILL is a psychometrically sound patient-reported outcome instrument, and the results further support its reliability and validity across all AMD stages. We recommend the shortened version of the questionnaire with three subscales (VILL-33) for future use., Trial Registration Number: NCT03349801., Competing Interests: Competing interests: JHT: Heidelberg Engineering, Optos, Carl Zeiss Meditec, CenterVueSGP: Heidelberg Engineering, Optos Carl Zeiss Meditec, CenterVue; CBe: None; MB: None; JC: None; DR: None; CBo: employee of Novartis; SP: employee of Novartis; UFOL: employee of F. Hoffmann-La Roche; SL: employee of Bayer; FGH: Acucela, Allergan, Apellis, Bayer, Boehringer-Ingelheim, Bioeq/Formycon, CenterVue, Ellex, Roche/Genentech, Geuder, Grayburg Vision, Heidelberg Engineering, Kanghong, LinBioscience, NightStarX, Novartis, Optos, Pixium Vision, Oxurion, Stealth BioTherapeutics, Zeiss; TB: None; JB: None; RPF: Bayer, Ellex, Novartis, Novartis, Opthea, Alimera, Santhera, Roche/Genentech, CentreVue, Zeiss., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Traffic-related air pollution can trigger myocardial infarction (MI). However, the hourly hazard period of exposure to nitrogen dioxide (NO 2 ), a common traffic tracer, for incident MI has not been fully evaluated. Thus, the current hourly US national air quality standard (100 ppb) is based on limited hourly-level effect estimates, which may not adequately protect cardiovascular health., Objectives: We characterized the hourly hazard period of NO 2 exposure for MI in New York state (NYS), USA, from 2000 to 2015., Methods: For nine cities in NYS, we obtained data on MI hospitalizations from the NYS Department of Health Statewide Planning and Research Cooperative System and hourly NO 2 concentrations from the US Environmental Protection Agency's Air Quality System database. We used city-wide exposures and a case-crossover study design with distributed lag non-linear terms to assess the relationship between hourly NO 2 concentrations over 24 h and MI, adjusting for hourly temperature and relative humidity., Results: The mean NO 2 concentration was 23.2 ppb (standard deviation: 12.6 ppb). In the six hours preceding MI, we found linearly increased risk with increasing NO 2 concentrations. At lag hour 0, a 10 ppb increase in NO 2 was associated with 0.2 % increased risk of MI (Rate Ratio [RR]: 1.002; 95 % Confidence Interval [CI]: 1.000, 1.004). We estimated a cumulative RR of 1.015 (95 % CI: 1.008, 1.021) for all 24 lag hours per 10 ppb increase in NO 2 . Lag hours 2-3 had consistently elevated risk ratios in sensitivity analyses., Conclusions: We found robust associations between hourly NO 2 exposure and MI risk at concentrations far lower than current hourly NO 2 national standards. Risk of MI was most elevated in the six hours after exposure, consistent with prior studies and experimental work evaluating physiologic responses after acute traffic exposure. Our findings suggest that current hourly standards may be insufficient to protect cardiovascular health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: Endovascular treatment is not recommended for aortic pathologies in patients with connective tissue diseases (CTDs) other than in redo operations and as bridging procedures in emergencies. However, recent developments in endovascular technology may challenge this dogma., Objective: To assess the midterm outcomes of endovascular aortic repair in patients with CTD., Design, Setting, and Participants: For this descriptive retrospective study, data on demographics, interventions, and short-term and midterm outcomes were collected from 18 aortic centers in Europe, Asia, North America, and New Zealand. Patients with CTD who had undergone endovascular aortic repair from 2005 to 2020 were included. Data were analyzed from December 2021 to November 2022., Exposure: All principal endovascular aortic repairs, including redo surgery and complex repairs of the aortic arch and visceral aorta., Main Outcomes and Measures: Short-term and midterm survival, rates of secondary procedures, and conversion to open repair., Results: In total, 171 patients were included: 142 with Marfan syndrome, 17 with Loeys-Dietz syndrome, and 12 with vascular Ehlers-Danlos syndrome (vEDS). Median (IQR) age was 49.9 years (37.9-59.0), and 107 patients (62.6%) were male. One hundred fifty-two (88.9%) were treated for aortic dissections and 19 (11.1%) for degenerative aneurysms. One hundred thirty-six patients (79.5%) had undergone open aortic surgery before the index endovascular repair. In 74 patients (43.3%), arch and/or visceral branches were included in the repair. Primary technical success was achieved in 168 patients (98.2%), and 30-day mortality was 2.9% (5 patients). Survival at 1 and 5 years was 96.2% and 80.6% for Marfan syndrome, 93.8% and 85.2% for Loeys-Dietz syndrome, and 75.0% and 43.8% for vEDS, respectively. After a median (IQR) follow-up of 4.7 years (1.9-9.2), 91 patients (53.2%) had undergone secondary procedures, of which 14 (8.2%) were open conversions., Conclusions and Relevance: This study found that endovascular aortic interventions, including redo procedures and complex repairs of the aortic arch and visceral aorta, in patients with CTD had a high rate of early technical success, low perioperative mortality, and a midterm survival rate comparable with reports of open aortic surgery in patients with CTD. The rate of secondary procedures was high, but few patients required conversion to open repair. Improvements in devices and techniques, as well as ongoing follow-up, may result in endovascular treatment for patients with CTD being included in guideline recommendations.

Objectives: To investigate incident cataract surgery and to investigate determinants of cataract surgery uptake in Chinese adults., Design: This nationally representative longitudinal study recorded self-reported incident cataract surgery, and measured biological, clinical and socioeconomical characteristics at baseline and endline., Setting: In the first stage, 150 county-level units were randomly chosen with a probability-proportional-to-size sampling technique from a sampling frame containing all county-level units. The sample was stratified by region and within region by urban district or rural county and per capita gross domestic product. The final sample of 150 counties fell within 28 provinces of China., Participants: Urban and rural Chinese persons aged 45 years and older., Primary and Secondary Outcome Measures: Incident cataract surgery (primary outcome) and the factors associated with incident cataract surgery (secondary outcome)., Results: Among 16 663 people enrolled in 2011, 13 705 (82.2%) attended follow-up in 2015. Among these, 167 (1.22%) reported incident cataract surgery. Those receiving surgery were significantly older (66.2±8.79 vs 58.3±9.18, p≤0.001) and more likely to report: illiteracy (44.9% vs 27.1%, p<0.001), poor baseline distance vision (49.7% vs 20.0%, p≤0.001), poor baseline near vision (37.1% vs 21.8%, p≤0.001), baseline visual impairment (15.6% vs 5.5%, p≤0.001), diabetes (12.0% vs 7.42%, p≤0.05) and higher baseline depression scores (9.7 vs 8.4 on a scale of 0-30, p≤0.05). In linear regression models, older age, worse distance vision, hypertension or diabetes, illiteracy and lower depression score were significantly associated with undergoing surgery. Results were similar in models including only persons aged ≥60 years, except that urban residence was also associated with surgery. When only those aged ≥60 years with poor vision were included, results were again the same, except that higher household expenditure was also associated with surgery., Conclusions: In China, cataract surgical rates remain low; underserved groups such as rural dwellers are less likely to receive cataract surgery., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The brown garden snail (Cornu aspersum) is a major agricultural pest, causing damage to a wide range of economically important crops. Withdrawal or restricted use of pollutant molluscicides like metaldehyde has prompted a search for more benign control products. This study investigated the response of snails to 3-octanone; a volatile organic compound (VOCs) produced by the insect pathogenic fungus Metarhizium brunneum. Concentrations of 1 - 1000 ppm of 3-octanone were first assessed in laboratory choice assays to determine behavioural response. Repellent activity was found at 1000 ppm whereas attractance was found for the lower concentrations of 1, 10 and 100 ppm. These three concentrations of 3-octanone were carried forward in field evaluations to assess potential for use in "lure and kill" strategies. The highest concentration (100 ppm) was the most attractive to the snails but also the most lethal. Even at the lowest concentration this compound proved toxic effects making 3-octanone an excellent candidate for the development as a snail attractant and molluscicide., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Wireworm, the larval stages of click beetles, are a serious pest of tubers, brassicas and other important commercial crops throughout the northern hemisphere. No effective control agent has been developed specifically for them, and many of the pesticides marketed as having secondary application against them have been withdrawn from EU and Asian markets. Metarhizium brunneum , an effective entomopathogenic fungus, and its derived volatile metabolites are known to be effective plant biostimulants and plant protectants, although field efficacy has yet to be validated. Field validation of a combined M. brunneum and derived VOC treatments was conducted in Wales, UK, to assess the effects of each as a wireworm control agent and biostimulant. Plots were treated with Tri-Soil ( Trichoderma atroviridae ), M. brunneum , 1-octen-3-ol or 3-octanone, or combinations thereof. Treatments were applied subsurface during potato seeding ( n = 52), and potatoes were harvested at the end of the growing season. Each potato was weighed individually and scored for levels of wireworm damage. Applications of both the VOCs and the M. brunneum individually were found to significantly decrease wireworm burden ( p < 0.001). Combinations of M. brunneum and 3-octanone were also found to significantly decrease wireworm damage ( p < 0.001), while no effect on yield was reported, resulting in an increased saleable mass over controls ( p < 0.001). Herein, we present a novel 'stimulate and deter' wireworm control strategy that can be used to significantly enhance saleable potato yields and control wireworm populations, even under high pest pressure densities.

Plant parasitic nematodes are a serious threat to crop production worldwide and their control is extremely challenging. Fungal volatile organic compounds (VOCs) provide an ecofriendly alternative to synthetic nematicides, many of which have been withdrawn due to the risks they pose to humans and the environment. This study investigated the biocidal properties of two fungal VOCs, 1-Octen-3-ol and 3-Octanone, against the widespread root-knot nematode Meloidogyne incognita . Both VOCs proved to be highly toxic to the infective second-stage juveniles (J2) and inhibited hatching. Toxicity was dependent on the dose and period of exposure. The LD50 of 1-Octen-3-ol and 3-Octanone was 3.2 and 4.6 µL, respectively. The LT50 of 1-Octen-3-ol and 3-Octanone was 71.2 and 147.1 min, respectively. Both VOCs were highly toxic but 1-Octen-3-ol was more effective than 3-Octanone. Exposure of M. incognita egg-masses for 48 h at two doses (0.8 and 3.2 µL) of these VOCs showed that 1-Octen-3-ol had significantly greater nematicidal activity (100%) than 3-Octanone (14.7%) and the nematicide metham sodium (6.1%). High levels of reactive oxygen species detected in J2 exposed to 1-Octen-3-ol and 3-Octanone suggest oxidative stress was one factor contributing to mortality and needs to be investigated further.

Background: The gene encoding the transcription factor, Grainyhead-like 3 (Grhl3), plays critical roles in mammalian development and homeostasis. Grhl3-null embryos exhibit thoraco-lumbo-sacral spina bifida and soft-tissue syndactyly. Additional studies reveal that these embryos also exhibit an epidermal proliferation/differentiation imbalance. This manifests as skin barrier defects resulting in peri-natal lethality and defective wound repair. Despite these extensive analyses of Grhl3 loss-of-function models, the consequences of gain-of-function of this gene have been difficult to achieve., Results: In this study, we generated a novel mouse model that expresses Grhl3 from a transgene integrated in the Rosa26 locus on an endogenous Grhl3-null background. Expression of the transgene rescues both the neurulation and skin barrier defects of the knockout mice, allowing survival into adulthood. Despite this, the mice are not normal, exhibiting a range of phenotypes attributable to dysregulated Grhl3 expression. In mice homozygous for the transgene, we observe a severe Shaker-Waltzer phenotype associated with hearing impairment. Micro-CT scanning of the inner ear revealed profound structural alterations underlying these phenotypes. In addition, these mice exhibit other developmental anomalies including hair loss, digit defects, and epidermal dysmorphogenesis., Conclusion: Taken together, these findings indicate that diverse developmental processes display low tolerance to dysregulation of Grhl3., (© 2022 The Authors. Developmental Dynamics published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

In Brazil, the production of beneficial microorganisms by growers exclusively for their own use is a practice known as "on-farm production". Regarding on-farm bioinsecticides, they were initially deployed for pests of perennial and semi-perennial crops in the 1970s but, since 2013, their use has extended to pests of annual crops such as maize, cotton, and soybean. Millions of hectares are currently being treated with these on-farm preparations. Local production reduces costs, meets local needs, and reduces inputs of environmentally damaging chemical pesticides, facilitating establishment of more sustainable agroecosystems. Critics argue that without implementation of stringent quality control measures there is the risk that the on-farm preparations: (1) are contaminated with microbes which may include human pathogens or (2) contain very little active ingredient, impacting on field efficacy. The on-farm fermentation of bacterial insecticides predominates, especially that of Bacillus thuringiensis targeting lepidopteran pests. However, there has been a rapid growth in the past 5 years in the production of entomopathogenic fungi, mostly for the control of sap-sucking insects such as whitefly (Bemisia tabaci (Gennadius)) and the corn leafhopper (Dalbulus maidis (DeLong and Wolcott)). In contrast, on-farm production of insect viruses has seen limited growth. Most of the ca. 5 million rural producers in Brazil own small or medium size properties and, although the vast majority still do not practice on-farm production of biopesticides, the topic has aroused interest among them. Many growers who adopt this practice usually use non-sterile containers as fermenters, resulting in poor-quality preparations, and cases of failure have been reported. On the other hand, some informal reports suggest on-farm preparations may be efficacious even when contaminated, what could be explained, at least partially, by the insecticidal secondary metabolites secreted by the pool of microorganisms in the liquid culture media. Indeed, there is insufficient information on efficacy and mode of action of these microbial biopesticides. It is usually the large farms, some with > 20,000 ha of continuous cultivated lands, that produce biopesticides with low levels of contamination, as many of them possess advanced production facilities and have access to specialized knowledge and trained staff. Uptake of on-farm biopesticides is expected to continue but the rate of adoption will depend on factors such as the selection of safe, virulent microbial strains and implementation of sound quality control measures (compliance with emerging Brazilian regulations and international standards). The challenges and opportunities of on-farm bioinsecticides are presented and discussed., (© 2023. Sociedade Entomológica do Brasil.)

Background: Achondroplasia, caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene, is the most common skeletal dysplasia. The Lifetime Impact of Achondroplasia Study in Europe (LIAISE; NCT03449368) aimed to quantify the burden of achondroplasia among individuals across a broad range of ages, including adults., Methods: Demographic, clinical and healthcare resource use data were collected from medical records of achondroplasia patients enrolled in 13 sites across six European countries in this retrospective, observational study. Descriptive statistics or event rates per 100 person-years were calculated and compared across age groups as well as by history of limb lengthening. Patient-reported outcomes (quality of life [QoL], pain, functional independence, work productivity and activity impairments) were evaluated using questionnaires at the time of enrolment. An exploratory analysis investigated correlations between height (z-score or centimetres) and patient-reported outcomes., Results: Overall, 186 study patients were included, with a mean age of 21.7 ± 17.3 years (range 5.0-84.4). At least one complication or surgery was reported for 94.6% and 72.0% of patients, respectively, at a rate of 66.6 and 21.5 events per 100 person-years. Diverse medical and surgical complications were reported for all ages in a bimodal distribution, occurring more frequently in the youngest and oldest age groups. A total of 40 patients had previously undergone limb lengthening (capped at 20% per the study protocol). The most frequent surgery types varied by age, in line with complication profiles. Healthcare resource use was high across all age groups, especially among the youngest and oldest individuals, and did not differ substantially according to history of limb lengthening. Compared to general population values, patients reported impaired QoL particularly for physical functioning domains. In addition, patients reported difficulty carrying out daily activities independently and pain starting in childhood. Patient height correlated with multiple patient-reported outcomes., Conclusions: The findings of this study suggest that, across an individual's lifetime, achondroplasia is associated with multisystem complications, reduced QoL and functionality, and increased pain. These results highlight the large amount of healthcare resources that individuals with achondroplasia require throughout their lifespans and provide novel insights into current achondroplasia management practices across Europe. Trial registration ClinicalTrials.gov, NCT03449368, Submitted 14 December 2017 - prospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT03449368., (© 2023. The Author(s).)

Aedes aegypti (Diptera: Culicidae) is the principal vector of dengue and other viruses that cause disease among 100 to 400 million people each year. The recent development of widespread insecticidal resistance has led to the rapid development of biological control solutions aimed at larval control. While the efficacy of Metarhizium brunneum has been shown against Aedes larvae, the impact of larval population dynamics will need to be determined to formulate effective control strategies. In this study, larvae were subjected to four concentrations of M. brunneum (105, 106, 107, 108 conidia ml-1). Larvae were found to be susceptible to M. brunneum with dose-dependent efficacy. When constant larval immigration was added as a parameter, peak mortality was consistently found to occur on the fourth day, before a significant reduction in control efficacy linked to a decline in conidial availability within the water column. This suggests that M. brunneum treatments should be applied at a concentration 1 × 107 conidia ml-1 every four days to effectively control mosquito larvae in the field, regardless of the fungal formulation, water volume, or larval density. Understanding fungal-mosquito dynamics is critical in developing appropriate control programs as it helps optimize the fungal control agent's dose and frequency of application., (© The Author(s) 2022. Published by Oxford University Press on behalf of Entomological Society of America.)

Objectives: Surgical distractions are associated with worse patient outcomes. Lung transplantation and cardiac surgery's multi-disciplinary nature, and their inherent complexities render them more vulnerable to distractions. We aim to use a novel distractions capture tool to evaluate the severity of distractions during cardiac surgery (CS) and lung transplantation (LTx) and assess its impact on post-operative complications., Methods: A prospective 'blinded' study was undertaken by direct observation of distractions during CS and LTx. Events were identified using the Imperial College Error Capture tool (ICECAP). Number and severity of distractions were correlated with post-operative outcomes (ICU & hospital stay, bleeding and anastomotic complications)., Results: In LTx, we observed 2059 distractions within 287 h across 41 surgeries. In CS, we observed 1089 distractions within 192 h across 62 surgeries. Surgeons were consciously aware of 19.2% (LTx) and 21.3% (CS) of recorded events. Distractions consisted of procedure-independent pressures (61% LTx vs 56% CS), equipment problems (15% LTx vs 23%CS), communication (12% LTx vs 12% CS), technical problems or patient safety concerns (12% LTx vs 9% CS). In CS, 91% of procedure-independent pressures were non-operative distractions whilst LTx recorded 83%. Staff absences at a critical moment of surgery were recorded at 9% (LTx) and 7% (CS). The number and severity of distractions correlated with bleeding (CS p < 0.001, LTx p < 0.01), prolonged ICU stay (CS p = 0.002, LTx p = 0.002), hospital stay (CS p < 0.001) and anastomotic complications(LTx p < 0.03)., Conclusions: ICECAP as a novel surgical distractions capture tool was effective & applicable to both elective cardiac and urgent transplant surgeries. Surgeons were unaware of a large number of distractions & interruptions. Distractions were associated with longer ICU stay and higher rate of bleeding., (© 2023. The Author(s).)

Background: Acute Compartment Syndrome (ACS) is a significant complication after revascularization for acute lower limb ischemia (ALI). High risk patients sometimes undergo prophylactic fasciotomy (PF) to prevent ACS. Patients that develop ACS undergo therapeutic fasciotomy (TF). The optimal timing of fasciotomy has been debated. The aim of this study was to describe and compare renal and wound outcomes in patients undergoing PF and TF., Methods: A retrospective cohort study including 76 patients undergoing PF (n = 40) or TF (n = 36) after revascularization for ALI between 2006 and 2018. Estimated glomerular filtration rate (e-GFR) was used to evaluate renal function and compare within (paired-samples t-test) and between (analysis of variance) groups. Wound complications and healing time were compiled from the complete wound healing period and compared between groups with Pearson's chi-squared-and log-rank test, respectively., Results: E-GFR improved over the in-hospital period with 8.2 ml/min/1.73 m 2 (95% confidence interval [CI] 2.4-14.1, P = 0.007) in the PF group and 4.4 ml/min/1.73 m 2 (95% CI 1.2-7.7, P = 0.010) in the TF group, with no significant difference between the 2 groups (0.3 ml/min/1.73 m 2 , 95% CI -6.7 to 7.4, P = 0.93). The wound infection rate was higher after TF (PF = 60.6 % and TF = 82.4 %, P = 0.048), whereas rate of other wound complications (PF = 61.3 % and TF = 35.3%, P = 0.036) was higher after PF., Conclusions: Overall wound complications were high, whereas renal function improved during in-hospital stay. A more conservative approach to fasciotomy could avoid unnecessary fasciotomies and reduce wound complications, while holding the potential to sufficiently preserve renal function if fasciotomy is needed for ACS. This would be possible and safe if an early diagnosis and treatment of ACS can be ensured., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background & Aims: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with a poor long-term prognosis. The molecular mechanisms underlying the initiation and progression of this tumor are largely unknown. The transcription factor GRHL3 functions as a potent tumor suppressor in SCC of skin, head, and neck. This study aims to determine whether GRHL3 also plays a role in the homeostasis of the esophageal epithelium and in the development of ESCC., Methods: The effects of Grhl3 deletion on squamous epithelial homeostasis in embryos and adult mice were examined using immunohistochemistry, transmission electron microscopy, and real-time polymerase chain reaction. The conditionally deleted mice were subsequently used to determine susceptibility to ESCC. Whole-transcriptome sequencing (RNA-seq) was performed on ESCC in wild-type and Grhl3 deleted animals. To decipher the signaling pathways, real-time polymerase chain reaction, immunohistochemistry, analysis of chromatin immunoprecipitation sequencing, chromatin immunoprecipitation-polymerase chain reaction, and RNA seq datasets were used. Primary human samples were used to validate the findings in the mouse model., Results: Loss of Grhl3 perturbs the proliferation-differentiation balance in the esophageal epithelium, thereby increasing the susceptibility to esophageal carcinogenesis in adult mice. Grhl3 imparts its tumor suppressor function by regulating the expression of HOPX. We have identified the Wnt/β-catenin pathway as the downstream effectors of GRHL3 and HOPX through our integrated approach using patient-derived ESCC samples and mouse models., Conclusions: GRHL3 conveys its tumor suppressor function in ESCC through regulating its target gene HOPX, which limits Wnt/β-catenin signaling. Targeted therapies to inhibit this pathway could be a potential treatment strategy for ESCC patients with reduced GRHL3 expression., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Neural tube closure is a dynamic morphogenic event in early embryonic development. Perturbations of this process through either environmental or genetic factors induce the severe congenital malformations known collectively as neural tube defects (NTDs). Deficiencies in maternal folate intake have long been associated with NTDs, as have mutations in critical neurulation genes that include the Grainyhead-like 3 (Grhl3) gene. Mice lacking this gene exhibit fully penetrant thoraco-lumbo-sacral spina bifida and a low incidence of exencephaly. Previous studies have shown that exposure of pregnant mice carrying hypomorphic Grhl3 alleles to exogenous retinoic acid (RA) increases the incidence and severity of NTDs in their offspring. Here, we demonstrate that inhibition of RA signaling using a high affinity pan-RA receptor antagonist administered to pregnant mice at E7.5 induces fully penetrant exencephaly and more severe spina bifida in Grhl3-null mice. Later administration, although prior to neural tube closure has no effect. Similarly, blockade of RA in the context of reduced expression of Grhl2, a related gene known to induce NTDs, has no effect. Taken together, these findings provide new insights into the complexities of the interplay between RA signaling and Grhl3-induced neurulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Achondroplasia is associated with disproportionate short stature and significant and potentially severe medical complications. Vosoritide is the first medicine to treat the underlying cause of achondroplasia and data from phase 3 and phase 2 extension studies showed effects on growth and body proportions. However, there are currently no long-term data available on the direct impact on endpoints such as medical complications and health-related quality of life (HRQoL). This study explored the perceived impact of achondroplasia on medical complications, HRQoL, healthcare resource use and mortality, and potential modifying effects of vosoritide, based on published evidence and expert opinion. Structured expert opinion was obtained by an international modified Delphi study among 14 experts in managing achondroplasia performed on a virtual platform and consisting of an explorative phase followed by an anonymous individual rating round., Results: Overall, the panelists expect that in individuals starting long-term treatment between 2 years of age and puberty, growth velocity increases observed in the clinical trials will be maintained until final height is reached (92% agreement) and will likely result in clinically meaningful improvements in upper-to-lower body segment ratio (85%). Earlier treatment initiation will likely result in a greater final height (100%) and more likely improve proportionality (92%) than later treatment. Although current data are limited, ≥ 75% of panelists find it conceivable that the earlier long-term treatment is started, the greater the probability of a positive effect on the lifetime incidence of symptomatic spinal stenosis, kyphosis, obstructive sleep apnea, and foramen magnum stenosis. These are among the most clinically important complications of achondroplasia because of their high impact on comorbidity, mortality, and/or HRQoL. A positive effect of vosoritide on the incidence of surgeries through lifetime was considered more likely with earlier long-term treatment (90%)., Conclusions: This explorative study, based on international expert opinion, provides further insight into the medical and functional impacts of achondroplasia and how these might be modified through long-term use of vosoritide. The results can be used to guide the direction and design of future research to validate the assumptions and to discuss potential treatment outcomes with disease modifying therapies with families and clinicians., (© 2022. The Author(s).)

Colistin minimum inhibitory concentration among Enterobacterales and Non-fermenters was determined using the new susceptibility method, Colistin Broth Disk Elution Method (CBDE), and its sensitivity and specificity. This descriptive cross-sectional study was conducted at Pakistan Railway Hospital, Rawalpindi from October 2020 to August 2021. Gram-negative bacteria were isolated and identified using Gram Stain and standard biochemical profile. Colistin Susceptibility was determined using CBDE and reference methods and then sensitivity and specificity of CBDE with standard reference methods. Essential and Categorical agreements were calculated. A total of 140 Gram-negative isolates were recovered from different specimens. The sensitivity and specificity of CBDE among Enterobacterales were 90.90% and 92.07% and for Pseudomonas aeruginosa 100% and 83.3% and for Acinetobacter baumannii 30% and 50% respectively. CBDE is simple, reliable, and cost effective to determine the colistin susceptibility among Enterobacterales and Pseudomonas aeruginosa while for Acinetobacter baumannii, this procedure is not useful. Key Words: Colistin susceptibility testing, CBDE, Enterobacterales, Non-fermenters.

Background: Conventional cost-effectiveness analysis [CEA] using cost per QALY thresholds may counteract other incentives introduced to foster development of treatments for rare and ultra-rare diseases. Therefore, alternative economic evaluation methods were explored, namely Discrete Choice Experiment Willingness to Pay (DCE-WTP) and Relative Social Willingness to Pay (RS-WTP), to value interventions for an ultra-rare childhood disease, Neuronal Ceroid Lipofuscinosis type 2 (CLN2)., Research Design and Methods: Treatment for CLN2 was valued from a citizen's ('social') perspective using DCE-WTP and RS-WTP in a survey of 4,009 United Kingdom [UK] adults. Three attributes (initial quality of life, treatment effect, and life expectancy) were used in both analyses. For DCE-WTP, a cost attribute (marginal income tax increase) was also included. Optimal econometric models were identified., Results: DCE-WTP indicated that UK adults are willing to pay incremental increases through taxation for improvements in CLN2 attributes. RS-WTP identified a willingness to allocate >40% of a pre-assigned healthcare budget to prevent child mortality and approximately 15% for improved health status., Conclusions: Both techniques illustrate substantive social WTP for CLN2 interventions, despite the small number of children benefitting. This highlights a gap between UK citizens' willingness to spend on rare disease interventions and current funding policies.

Objective: Satisfaction with healthcare may be captured by surveys of patients and staff, or in extreme cases, the number and severity of medical disputes. This study tries to investigate the relationship between satisfaction and hospital management as well as the role of good management in preventing medical disputes ex ante., Method: We investigate this relationship using information on management practices collected from 510 hospitals in mainland China using the World Management Survey questionnaire and combined with medical malpractice litigation data and patient/staff satisfaction surveys. Multiple regression models were used to analyse the relationship between hospital management scores and medical litigation outcomes as well as patient and staff satisfaction during 2014-2016., Results: An increase of one standard deviation in the management score was related to 13.1% (p < 0.10) lower incidence of medical disputes, 12.4% (p < 0.05) fewer medical litigations, and 51.3% (p < 0.10) less compensation. Better management quality of hospitals was associated with higher inpatient satisfaction (p < 0.05) and staff well-being (p < 0.01)., Conclusion: Improving hospital management could reduce hospital costs generated by lawsuits, reduce potential harm to patients, and improve patient and staff satisfaction, thus leading to a better patient-physician relationship., (© 2021 John Wiley & Sons Ltd.)

Background: Patients with diabetes mellitus (DM) have a more extensive distal arterial occlusive disease compared to non-diabetic patients. Diagnostic imaging is a necessity to identify the location and extent of the arterial occlusion in acute limb ischemia (ALI). Computed tomography angiography (CTA) is the most commonly used modality and the diagnostic performance with CTA of calf arteries may be questioned., Purpose: To evaluate diagnostic performance of CTA of calf arteries in ALI and to compare patients with and without DM., Material and Methods: All thrombolytic treatments performed during 2001-2018 in patients with ALI were included. Initial digital subtraction angiography (DSA) and CTA of all patients were classified according to the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) below-the-knee arteries and compared to CTA. Two raters assessed the CTA images independently. Inter-rater reliability was expressed as intraclass correlation (ICC) with 95% confidence intervals (CI)., Results: Patients with (n = 23) and without (n = 85) DM had lower ( P  = 0.006) glomerular filtration rate. ICC between CTA and DSA was 0.33 (95% CI -0.22 to 0.56) and 0.71 (95% CI 0.38-0.68) in patients with and without DM, respectively. Sensitivity with CTA for TASC D lesions in patients with and without DM was 0.14 (95% CI -0.12 to 0.40) and 0.64 (95% CI 0.48-0.80), respectively., Conclusion: The sensitivity of CTA for assessment of infra-popliteal TASC D lesions in patients with ALI was not acceptable in patients with DM in contrast to those without DM. Another imaging option at present times should be considered for patients with DM.

Vision impairment (VI) can have wide ranging economic impact on individuals, households, and health systems. The aim of this systematic review was to describe and summarise the costs associated with VI and its major causes. We searched MEDLINE (16 November 2019), National Health Service Economic Evaluation Database, the Database of Abstracts of Reviews of Effects and the Health Technology Assessment database (12 December 2019) for partial or full economic evaluation studies, published between 1 January 2000 and the search dates, reporting cost data for participants with VI due to an unspecified cause or one of the seven leading causes globally: cataract, uncorrected refractive error, diabetic retinopathy, glaucoma, age-related macular degeneration, corneal opacity, trachoma. The search was repeated on 20 January 2022 to identify studies published since our initial search. Included studies were quality appraised using the British Medical Journal Checklist for economic submissions adapted for cost of illness studies. Results were synthesized in a structured narrative. Of the 138 included studies, 38 reported cost estimates for VI due to an unspecified cause and 100 reported costs for one of the leading causes. These 138 studies provided 155 regional cost estimates. Fourteen studies reported global data; 103/155 (66%) regional estimates were from high-income countries. Costs were most commonly reported using a societal ( n  = 48) or healthcare system perspective ( n  = 25). Most studies included only a limited number of cost components. Large variations in methodology and reporting across studies meant cost estimates varied considerably. The average quality assessment score was 78% (range 35-100%); the most common weaknesses were the lack of sensitivity analysis and insufficient disaggregation of costs. There was substantial variation across studies in average treatment costs per patient for most conditions, including refractive error correction (range $12-$201 ppp), cataract surgery (range $54-$3654 ppp), glaucoma (range $351-$1354 ppp) and AMD (range $2209-$7524 ppp). Future cost estimates of the economic burden of VI and its major causes will be improved by the development and adoption of a reference case for eye health. This could then be used in regular studies, particularly in countries with data gaps, including low- and middle-income countries in Asia, Eastern Europe, Oceania, Latin America and sub-Saharan Africa., Competing Interests: MJB reports grants, in support of the work for The Lancet Global Health Commission on Global Eye Health, from The Queen Elizabeth Diamond Jubilee Trust, The Wellcome Trust, Moorfields Eye Charity (GR001061), Sightsavers, The Fred Hollows Foundation, The SEVA Foundation, The British Council for the Prevention of Blindness, and Christian Blind Mission. MJB is supported by the Wellcome Trust (207472/Z/17/Z). PK reports grants from Wellcome Trust, The Helen Hamlyn Trust, UCL Technology Fund, Moorfields Eye Charity, The Jules Thorn Charitable Trust, Fight for Sight, National Institute for Health Research, Apollo Therapeutics Fund, Medical Research Council, personal fees from Aerie, Alcon, CMER Hospital Group, Genetech, Glaukos, ISA RNA Therapeutics GmBH, Novartis, Santen, and Thea outside of the submitted work; having a patent pending for Biochannel Device, PK Eye Model, Moorfields UCL MIO Muller stem cells; participation on advisory boards for (Novartis, DrugTech, Santen, CRICK Institute, Decisions in health Care to Introduce or Diffuse innovations using Evidence); being a board member of Moorfields Eye Hospital, Ophthalmology Foundation Board, UCL Partners Academic Health Science Centre, UCLP Informatics Board; being a member of Clinical Research Coalition Group, AHSC Planning & Performance Executive, UCL IOO & Moorfields Joint Campaign and Steering Group, Faculty of Brain Sciences Heads of Research Departments Board, Joint Research Governance Committee, AHSC and AHSN Programme Directors Forum, Moorfields Eye Hospital and UCL Institute of Ophthalmology, R&D Advisory Group of Central & East London Local Clinical Research Network, Joint Research Strategy Committee, Moorfields Eye Hospital Institute of Ophthalmology, Research Management Committee, Moorfields Eye Hospital; being a director of NIHR Biomedical Research Centre for Ophthalmology; being on the grant panel of Moorfields Eye Charity, ICO-Allergan Research Fellowship Program, Alcon Research Institute Scientific Select Committee, Ruskell Medal Reviewer Committee, Worshipful Company of Spectacle; being a founder of and stockholding for Radiance Therapeutics and Optceutics; being a co-founder of Lumemed Let and being a private clinician at Moorfields Private., (© 2022 The Authors.)

Most amyotrophic lateral sclerosis (ALS) cases are sporadic (∼90%) and environmental exposures are implicated in their etiology. Large industrial facilities are permitted the airborne release of certain chemicals with hazardous properties and report the amounts to the US Environmental Protection Agency (EPA) as part of its Toxics Release Inventory (TRI) monitoring program. The objective of this project was to identify industrial chemicals released into the air that may be associated with ALS etiology. We geospatially estimated residential exposure to contaminants using a de-identified medical claims database, the SYMPHONY Integrated Dataverse®, with ∼26,000 nationally distributed ALS patients, and non-ALS controls matched for age and gender. We mapped TRI data on industrial releases of 523 airborne contaminants to estimate local residential exposure and used a dynamic categorization algorithm to solve the problem of zero-inflation in the dataset. In an independent validation study, we used residential histories to estimate exposure in each year prior to diagnosis. Air releases with positive associations in both the SYMPHONY analysis and the spatio-temporal validation study included styrene (false discovery rate (FDR) 5.4e-5), chromium (FDR 2.4e-4), nickel (FDR 1.6e-3), and dichloromethane (FDR 4.8e-4). Using a large de-identified healthcare claims dataset, we identified geospatial environmental contaminants associated with ALS. The analytic pipeline used may be applied to other diseases and identify novel targets for exposure mitigation. Our results support the future evaluation of these environmental chemicals as potential etiologic contributors to sporadic ALS risk., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The complexity of hazards, risk and environmental legislation surrounding the reuse of brownfield sites necessitates a preliminary risk assessment prior to their redevelopment. Most prevailing efforts have been targeted at indepth site investigations, which are often costly, time-consuming, and may not be required at the early stages of a site development. However, there is a collective absence of knowledge, methods and computer models that can present a complete framework to carry out a preliminary risk assessment that is simpler, quicker and sufficient, not only for risk assessor but also effectively communicative for a diverse range of stakeholders with or without risk assessment expertise. Therefore, this study aims to bridge this gap by designing and creating a framework, by not only identifying hazards but also exposing the degree of presence. Sixty-five potential hazards have been identified from a comprehensive literature review. A questionnaire survey was then shared with brownfield site experts (n = 76) that asked then to rank the priority of the potential hazards. Kendall's W test and Kruskal-Wallis H test were subsequently conducted to determine the level of agreement among the respondents. Mean weightings were calculated by using the Voting Analytic Hierarchy Process (VAHP) to prioritize the potential hazards from 'more likely' to 'least likely'. Based on this information, the framework has been developed. It is anticipated that the framework can assist professionals to conduct a preliminary assessment of brownfield sites, which enables them to gain informative and rapid guidance on any potential liabilities or risks related to a site's suitability for acquisition or redevelopment. In this context, the framework outlines a systematic structure to collect appropriate data and information in the three main categories which are sources, pathways and receptors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

PurposeRepetitive iodinated contrast media exposure may be harmful for the kidneys. The aim of the present study was to evaluate if patients with diabetes mellitus (DM) undergoing CT angiography (CTA) and local continuous thrombolysis for acute lower limb ischemia (ALI) had an increased risk of developing contrast-associated acute kidney injury (CA-AKI) compared to patients without DM. Methods: This is a retrospective study of patients undergoing CTA and local continuous thrombolysis due to ALI between 2001 and 2018. CA-AKI was defined as a 25% increase in serum creatinine within 72 hours after latest contrast administration. Results: There was no difference ( P = .30) in the frequency of CA-AKI between patients with (27.9%; n = 43) and without DM (20.6%; n = 170). Among patients with CA-AKI, patients with DM had a lower ( P < .001) estimated glomerular filtration rate (eGFR) at discharge (55 ml/min/1.73 m 2 ) than at admission (70 ml/min/1.73 m 2 ), while no such difference was found in the group without DM ( P = .20). The gram-iodine dose/eGFR ratio was higher ( P < .001) in patients with CA-AKI (median 1.49, [IQR 1.34-1.81]) than in those who did not develop CA-AKI (median 1.05 [IQR 1.00-1.13]). There was a trend that gram-iodine dose/eGFR ratio (OR 1.42/standard deviation increment, 95% CI 1.00-2.02; P = .050) was associated with an increased risk of CA-AKI, after adjusting for DM, age, and gender. Conclusions: The frequency of CA-AKI was high after CTA and local continuous thrombolysis for ALI without shown increased frequency for the DM group. Among patients with CA-AKI, however, patients with DM had worse renal function at discharge than those without DM. The gram-iodine dose/eGFR ratio in these patients needs to be lower to improve renal outcomes, particularly in patients with DM.

There has been selective pressure to maintain a skin barrier since terrestrial animals evolved 360 million years ago. These animals acquired an unique integumentary system with a keratinized, stratified, squamous epithelium surface barrier. The barrier protects against dehydration and entry of microbes and toxins. The skin barrier centres on the stratum corneum layer of the epidermis and consists of cornified envelopes cemented by the intercorneocyte lipid matrix. Multiple components of the barrier undergo cross-linking by transglutaminase (TGM) enzymes, while keratins provide additional mechanical strength. Cellular tight junctions also are crucial for barrier integrity. The grainyhead-like (GRHL) transcription factors regulate the formation and maintenance of the integument in diverse species. GRHL3 is essential for formation of the skin barrier during embryonic development, whereas GRHL1 maintains the skin barrier postnatally. This is achieved by transactivation of Tgm1 and Tgm5, respectively. In addition to its barrier function, GRHL3 plays key roles in wound repair and as an epidermal tumour suppressor. In its former role, GRHL3 activates the planar cell polarity signalling pathway to mediate wound healing by providing directional migration cues. In squamous epithelium, GRHL3 regulates the balance between proliferation and differentiation, and its loss induces squamous cell carcinoma (SCC). In the skin, this is mediated through increased expression of MIR21, which reduces the expression levels of GRHL3 and its direct target, PTEN, leading to activation of the PI3K-AKT signalling pathway. These data position the GRHL family as master regulators of epidermal homeostasis across a vast gulf of evolutionary history., (© 2021 ESVD and ACVD.)

The SAGA coactivator complex is essential for eukaryotic transcription and comprises four distinct modules, one of which contains the ubiquitin hydrolase USP22. In yeast, the USP22 ortholog deubiquitylates H2B, resulting in Pol II Ser2 phosphorylation and subsequent transcriptional elongation. In contrast to this H2B-associated role in transcription, we report here that human USP22 contributes to the early stages of stimulus-responsive transcription, where USP22 is required for pre-initiation complex (PIC) stability. Specifically, USP22 maintains long-range enhancer-promoter contacts and controls loading of Mediator tail and general transcription factors (GTFs) onto promoters, with Mediator core recruitment being USP22-independent. In addition, we identify Mediator tail subunits MED16 and MED24 and the Pol II subunit RBP1 as potential non-histone substrates of USP22. Overall, these findings define a role for human SAGA within the earliest steps of transcription., (© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

The "trainee in difficulty" (TID) can have multiple causative factors which can impact the delivery of an expected standard of skill sets. The communication and interpersonal skills in Emergency Department (ED) setting are key to any trainee's performance in an ED environment where team playing is a major factor in achieving safe and holistic care for patients. Trainer or a young faculty member responsible for the training may not have the emotional intelligence or experience to deal with all the issues faced by the TID. This paper talks about the difficulties faced by an experienced trainee in difficulty, who has changed his career from an experienced ED nurse to a trainee registrar in Emergency Medicine. The second case study is about a young emergency medicine residency program director who fails to appropriately address a trainee's situation and compounds the trainees' issues. The effect of honest, transparent communication of an educational supervisor and setting clear goals for the TID can have a huge impact on trainees' performance. A residency program director's inexperience and poor skills to deal and escalate the trainee's issues may jeopardize a young physicians' career., Competing Interests: The case studies regarding trainee in difficulty have been written solely for educational purposes and there has been no other reason, intention or conflict of interest., (© 2020 Publishing services provided by Elsevier B.V. on behalf of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.)

Background: Utility studies enable preference-based quantification of a disease's impact on patients' health-related quality of life (HRQoL). It is often difficult to obtain utility values for rare, neurodegenerative conditions due to cognitive burden of direct elicitation methods, and the limited size of patient/caregiver populations. CLN2 disease (neuronal ceroid lipofuscinosis type 2) is an ultra-rare, progressive condition, for which there are no published utility data fully capturing all disease stages. This case study demonstrates how utility values can be estimated for ultra-rare paediatric diseases by asking clinicians to complete EQ-5D-5L questionnaires based on vignettes describing the stages of CLN2 disease., Methods: An indirect elicitation method using proxy-reporting by clinical experts was adopted. Eighteen vignettes were developed, describing nine progressive disease stages as defined by motor and language domain scores of the CLN2 Clinical Rating Scale, in individuals treated with cerliponase alfa or standard care. Eight clinical experts with experience of treating CLN2 disease with cerliponase alfa and current standard care completed the proxy version 2 EQ-5D-5L online after reading these vignettes. Resulting scores were converted to EQ-5D-5L utility values for each disease stage, using UK, German and Spanish value sets., Results: Utility values, which are typically anchored by 0 (equivalent to death) and 1 (full health), decreased with CLN2 disease progression (results spanned the maximum range of the utility scale). Assigned utility values were consistently higher for patients receiving cerliponase alfa than standard care; differences were statistically significant for the 6 most severe disease stages (p < 0.05). Analysis of the individual dimensions of the EQ-5D-5L showed that greatest differences between patients treated with cerliponase alfa and standard care occurred in the pain dimension (differences in mean scores ranged between no difference and 1.8), with notable differences also observed in the anxiety/depression dimension (differences in mean scores ranged between 0.1 and 1.0)., Conclusions: This study demonstrates a feasible methodology for eliciting utility values in CLN2 disease, indicating HRQoL declines with disease progression. Vignettes describing patients receiving cerliponase alfa were consistently assigned higher utility values for the same disease state, suggesting this treatment improves HRQoL compared with standard care. Trial registration NCT01907087, NCT02485899.

The entomopathogenic fungus (EPF) Metarhizium brunneum occupies the same ecological niche as entomopathogenic nematodes (EPN), with both competing for insects as a food source in the rhizosphere. Interactions between these biocontrol agents can be antagonistic or synergistic. To better understand these interactions, this study focussed on investigating the effect of M. brunneum volatile organic compounds (VOCs), 1-octen-3-ol and 3-octanone, on EPN survival and behaviour. These VOCs proved to be highly toxic to the infective juveniles (IJs) of the EPN Steinernema carpocapsae , Steinernema feltiae and Heterorhabditis bacteriophora with mortality being dose dependent. Chemotaxis studies of H. bacteriophora IJs in Pluronic F127 gel revealed significant preference for the VOCs compared with controls for all tested concentrations. The VOCs also impacted on the test insects in a dose-dependent manner with 3-octanone being more toxic to Galleria mellonella , Cydia splendana and Curculio elephas larvae than 1-octen-3-ol. Mortality of C. splendana and G. mellonella larvae was significantly higher when exposed to relatively high doses (>25%) of 3-octanone. Lower doses of 3-octanone and 1-octen-3-ol immobilised test insects, which recovered after exposure to fresh air for 2 hrs. In depth studies on H. bacteriophora showed that exposure of IJs to > 10% concentration of 3-octanone or 1-octen-3-ol negatively affected infectivity whereas exposure to lower doses (0.1%, 0.01%) had no effect. The VOCs affected IJs, reducing penetration efficacy and the number of generations inside G. mellonella but they failed to inhibit the bacterial symbiont, Photorhabdus kayaii . The ecological significance of VOCs and how they could influence EPF-EPN insect interactions is discussed., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

Context: No brief patient-reported experience measure focuses on the most significant concerns of seriously ill individuals., Objectives: The objective of the study was to develop the consideRATE questions., Methods: This user-centered design study had three phases. We reviewed the literature and consulted stakeholders, including caregivers, clinicians, and researchers, to identify the elements of care most important to patients (Phase 1). We refined items based on cognitive interviews with patients, families, and clinicians (Phase 2). We piloted the measure with patients and families (Phase 3)., Results: Phase 1 resulted in seven questions addressing the following elements: 1) care team attention to patients' physical symptoms, 2) emotional symptoms, 3) environment of care, 4) respect for patients' priorities, 5) communication about future plans, 6) communication about financial and similar affairs, and 7) communication about illness trajectory. Phase 2 participants included eight patients, eight family members, and seven clinicians. We added an open-text comment option. We did not identify any other issues that were important enough to participants to include. Response choices ranged from one (very bad) to four (very good), with a not applicable option (does not apply). Phase 3 involved 15 patients and 16 family members and demonstrated the acceptability of the consideRATE questions. Most reported that the questions were not distressing, disruptive, or confusing. Completion time averaged 2.4 minutes (range 1-5)., Conclusion: Our brief patient-reported serious illness experience measure is based on what matters most to patients, families, and clinicians. It was acceptable to patients and families in a regional sample. It has promise for use in clinical settings., (Copyright © 2020. Published by Elsevier Inc.)

Local communities are struggling with persistent health inequities driven by income disparity, housing inadequacy, and other intersecting factors that constrain individual and community well-being. Increasingly, intersectoral approaches are recognized as essential to tackle such challenges, given their intersecting nature. This paper describes Equity-focused Intersectoral Practice (EquIP), a novel methodology that merges participatory research principles with the purposeful positioning of grounded expertise (lived experience) to shift the gaze of intersectoral actors towards the contextual factors that contribute to health inequities. The EquIP methodology creates uncommon spaces for intersectoral encounter that support critical reflexivity and relationship-building among institutional and community-based intersectoral actors. A case example of the EquIP methodology, implemented in a small, rural Canadian city in the context of a regional housing crisis, illustrates how investment in reflexivity and relational praxis among diverse intersectoral actors supports the identification of existing structures, beliefs, and practices within institutional settings that constrain effective intersectoral response to health inequities., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Root knot nematodes (RKNs) cause significant crop losses. Although RKNs and entomopathogenic fungi, such as Metarhizium brunneum , are associated with plant roots, very little is known about the interactions between these two organisms. This study showed that conidia and VOCs of Me. brunneum influenced the behaviour of M. hapla . The response was dependent on the fungal strain, VOC, concentration of both VOC and conidia, and time. Tomatoes planted in soil treated with the highest doses of conidia usually had a higher number of nematodes than untreated control plants. This was particularly obvious for Me. brunneum strain ARSEF 4556, 7 and 14-days post-treatment. The VOCs, 1-octen-3-ol and 3-octanone, lured M. hapla to plants when used at low doses and repelled them at high doses. In Petri dish assays. the VOCs 1-octen-3-ol and 3-octanone, caused 100% mortality of M. hapla at the highest dose tested (20 µl). Very few live M. hapla were recovered from soil treated with the VOC 1-octen-3-ol, especially at the highest doses tested., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)